Synthesis, detection and quantification of the highly active AhR ligands tryptanthrin, indirubin and indolo[3,2-b]carbazol in Malassezia yeasts

Malassezia yeasts are part of human skin microbiota and can become pathogenic under currently unclarified conditions. HPLC/UV combined with LC-MS/MS analysis of the extracts of several Malassezia species, revealed the production of compounds like indolo[3,2-b]carbazol (ICZ) [1], indirubin [2] and tryptanthrin[3], which are among the most active Aryl-hydrocarbon Receptor (AhR) inducers known and, interestingly, are preferentially biosynthesized by Malassezia furfur isolates from diseased skin. A previously reported by our group biomimetic synthesis, from indole-3-carboxaldehyde (I3A), the main metabolic product of tryptophan found in all Malassezia studied species, to indirubin and trypranthrin simultaneously [3], showed a common biosynthetic path for these two metabolites. This reaction is a one-step oxidation, using hydrogen peroxide and diphenyldiselenide as a catalyst. The synthesis of the above indole alkaloids allowed us to proceed not only to their quantification by HPLC analysis, but also to the further examination of this biomimetic reaction. Surprisingly, the formation of the same metabolites was achieved even when simple indole was used as starting material. This gave us the opportunity to synthesize a series of symmetric indirubin and tryptanthrin analogues, beginning from the appropriately substituted indoles. Although AhR is an orphan receptor, there are increasing data about its relation with skin homeostasis and skin nosology. Based on our previous work on the activation of AhR in HaCaT cells by Malassezia extracts [3] we could propose that the presence on the human skin of microorganisms able to constantly synthesize potent AhR ligands may play a crucial role in the development of skin diseases.